Sustained-release buprenorphine solutions

ABSTRACT

The disclosure provides extended release pharmaceutical formulations comprising an opioid, particularly buprenorphine, a biocompatible organic solvent, and, optionally, a glycol, for use in the treatment of pain or opioid dependence. The pharmaceutical formulations are in the form of a pharmaceutical solution.

RELATED APPLICATIONS

This application is the national stage filing under USC 371 ofinternational application PCT/GB2015/050676 filed on Mar. 9, 2015, whichclaims priority to United Kingdom Application No. 1404139.6 filed Mar.10, 2014, the disclosures of which are incorporated by reference hereinin their entirety.

FIELD

This disclosure relates to sustained-release pharmaceutical formulationscomprising a solution of an opioid and a biocompatible organic solvent.The pharmaceutical formulations are capable of providing sustainedrelease of an opioid for a period of at least one month after a singleinjection into a patient. The pharmaceutical formulations are useful forthe treatment of pain and opioid dependence.

BACKGROUND

Buprenorphine (also known as(2S)-2-[(−)-(5R,6R,7R,14S)-9a-cyclo-propyl-methyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-di-methylbutan-2-oland marketed under the trade names SUBUTEX® (buprenorphine by IndiviorPLC) and SUBOXONE® (buprenorphine/naloxone by Indivior PLC) for thetreatment of opioid dependence. These products are in tablet and filmformulations and are intended to deliver daily therapeutic levels ofbuprenorphine and are taken either buccally or sublingually. However,there are often issues with diversion in patients with an opioiddependence problem. There is a need therefore for a longer term,non-divertible method of administering buprenorphine which delivers aconstant and effective dose of buprenorphine to the patient over aperiod of a month or longer, and which does not result in anaccumulation of buprenorphine in the patient's metabolism.

Various sustained release methods are employed in the pharmaceuticalindustry, for example, a non-degradable buprenorphine implant,PROBUPHINE® (Titan Pharmaceuticals), has been shown to releasebuprenorphine for six months once implanted in patients. Although theimplant may be efficacious to treat opioid dependence (Ling et al, JAMA,304(14):1576-83 (2010)), it requires surgical procedure for placement inthe patent and a second surgical procedure to remove the empty reservoirfrom the patient.

A biodegradable buprenorphine delivery system that can be easilyinjected and requires no surgical removal has also been investigated.Sigmon et al, Addiction, 101:420-432 (2006) reported a biodegradablepolymer microcapsule depot system that was able to sustain plasmabuprenorphine levels for at least 4 weeks after a single intramuscularinjection. Such microcapsule systems, however, can only be produced by acomplex manufacture process.

A flowable biodegradable liquid system is disclosed in WO 2011/154724.This system utilizes a biodegradable polymer, a biocompatible solvent,and buprenorphine, all solubilized as an injectable liquid that canslowly release buprenorphine for one month or longer. This system formsa solid implant in situ following injection.

US Publication No. 2013/0190341 discloses a lipid-based precursorformulation that utilizes phosphatidyl choline and glycerol dioleate toform a liquid crystal phase to control the release of buprenorphine. Inorder to make the formulation injectable, ethanol was added to dissolveall the components, including buprenorphine, to form a solution. Such asolution may provide buprenorphine plasma levels for up to 2 weeks aftera single subcutaneous injection.

WO 2007/103185 discloses rapid-release buprenorphine suspensions invarious solvent systems that form drug depots at the injection sites.The solvent systems include aqueous solutions and water immisciblesesame oil as well as water miscible organic solvents such as citricacid esters and polyethylene glycol. The slowest release formulationexemplified in the application released 53.97% buprenorphine in 6 daysin mice, and achieved an analgesic effect for 4 to 5 days.

WO 2011/154725 describes buprenorphine aqueous suspensions containingsurfactants with high buprenorphine drug loadings of 10% or more. Thosesuspensions appear to continuously release buprenorphine for about amonth in rats and 14 to 20 days in dogs after a single subcutaneous orintramuscular injection.

Although all the systems described above allegedly provide sustainedrelease of buprenorphine, there is still a need to develop bettersustained release formulations of buprenorphine that are easy to prepareand easy to inject, with better release kinetics, and that can last atleast a month or longer.

SUMMARY

The disclosure provides non-polymeric, opioid formulations that arecapable of delivering a therapeutically effective amount of an opioid toa patient for at least a month. The formulations comprise a solution of(i) a therapeutically effective amount of an opioid; (ii) abiocompatible organic solvent; and (iii) optionally a glycol. The opioidis preferably an opioid agonist, such as buprenorphine, morphine,hydromorphone, fentanyl, oxycodone, hydrocodone, meperidine, codeine,methadone, diphenoxylate, or propoxyphene. The biocompatible organicsolvent can be any known in the art, such as N-methyl-2-pyrrolidone,dimethyl acetamide, dimethyl sulfoxide, or a combination of two or morethereof. The glycol can be any known in the art, such as a polyethyleneglycol, a propylene glycol, or a combination thereof.

According to one aspect of the invention there is provided apharmaceutical solution comprising, consisting essentially of, orconsisting of: (i) at least 5 wt % buprenorphine in the form of a freebase or a pharmaceutically acceptable salt, and (ii) a biocompatibleorganic solvent selected from the group consisting ofN-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide, and acombination of two or more thereof; wherein the pharmaceutical solutiondoes not comprise a biodegradable polymer. In one embodiment thesolution comprises at least 8 wt % buprenorphine, for example at least 9wt % or at least 10 wt %.

In one embodiment there is provided a composition comprising a solutionof 5-55 wt % of buprenorphine dissolved in a biocompatible organicsolvent selected from N-methyl-2-pyrrolidone (NMP), dimethyl acetamide(DMAC), or dimethyl sulfoxide (DMSO) wherein the composition does notcomprise any biodegradable polymer.

In one embodiment, the disclosure provides formulations comprising,consisting essentially of, or consisting of: (i) 10 wt % to 55 wt %buprenorphine in the form of a free base or a pharmaceuticallyacceptable salt; (ii) a biocompatible organic solvent selected from thegroup consisting of N-methyl-2-pyrrolidone, dimethyl acetamide, dimethylsulfoxide, and a combination of two or more thereof; (iii) optionally aglycol, for example a glycol selected from the group consisting of apolyethylene glycol, a propylene glycol, or a combination thereof; (iv)optionally water; and (v) optionally an antioxidant; wherein theformulation does not comprise a biodegradable polymer. When a glycol ispresent, the weight ratio of (i):(ii):(iii) may be from 1:3:7 to1:0.5:0.1. Optionally the weight ratio of (i):(ii):(iii) may be from1:2.7:6.3 to 1:0.74:0.08. The formulations may be used to treat opioiddependence or pain.

These and other aspects of the invention are described in more detailherein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates buprenorphine release and plasma levels aftersubcutaneous injection of buprenorphine solutions in rats. In FIG. 1 theopen square and open circle data points refer to the % buprenorphinereleased and the solid circle and solid square data points refer to thebuprenorphine plasma levels.

FIG. 2 illustrates buprenorphine plasma profiles after subcutaneousinjection of two buprenorphine solutions at 60 mg buprenorphine dose intwo groups of dogs.

FIG. 3 illustrates buprenorphine plasma profiles after subcutaneousinjection of a 25 wt % buprenorphine solution at buprenorphine doses of10 mg, 30 mg, and 60 mg in three groups of dogs.

FIG. 4 illustrates buprenorphine plasma profiles after subcutaneousinjection of three different buprenorphine solutions at a buprenorphinedose of 60 mg in three groups of dogs.

DETAILED DESCRIPTION

Surprisingly, it has been found that a solution of an opioid, such asbuprenorphine, at a relatively high concentration in a biocompatibleorganic solvent, such as N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAC), or dimethyl sulfoxide (DMSO), without any releasemodifying agents, such as biodegradable or non-degradable polymers, andwithout any complexing agents, such as cyclodextrin, can provideconstant and prolonged opioid release for at least one month after asingle subcutaneous injection in animals.

One aspect of the invention provides a pharmaceutical solutioncomprising: (i) at least 5 wt % buprenorphine in the form of a free baseor a pharmaceutically acceptable salt, and (ii) a biocompatible organicsolvent selected from the group consisting of N-methyl-2-pyrrolidone,dimethyl acetamide, dimethyl sulfoxide, and a combination of two or morethereof; wherein the pharmaceutical solution does not comprise abiodegradable polymer.

The solution may comprise at least 6 wt %, at least 7 wt %, at least 8wt %, at least 9 wt %, at or least 10 wt % buprenorphine in the form ofa free base or a pharmaceutically acceptable salt. Solutions comprisinga high concentration (for example, at least 5 wt %) of buprenorphine inthe biocompatible organic solvent exhibit a low initial burst followingsubcutaneous administration of the solution to a subject. In particularsolutions comprising at least 8 wt %, for example at least 9 wt %, orparticularly, at least 10 wt % buprenorphine have been found to exhibita low initial burst following subcutaneous administration of thesolution. By “initial burst” is meant the initial release ofbuprenorphine from the solution shortly after subcutaneousadministration of the solution, for example 24 hours afteradministration of the solution. The initial burst may be determined asillustrated in the examples. For example, the initial burst may beestimated from PK data by measuring the ratio of the area under thecurve (AUC) in the initial 24 hours: the total AUC over the duration ofrelease from the solution (i.e AUC_(0-∞) (or an approximation thereof,for example AUC₀₋₂₈ days, AUC₀₋₁₂₂ days or AUC₀₋₁₇₈ days) in bloodplasma. Suitably the initial burst is less than 10%, for example lessthan 5%, less than 4.5%, less than 4%, less than 3.5% or less than 3% byweight of the buprenorphine administered to a subject is released fromthe solution in the 24 hours following subcutaneous administration ofthe solution. For example, the initial burst may be from about 1% toabout 10%, from about 1.5% to about 6%, from about 2% to about 5%, fromabout 1.5% to about 4.5% by weight of buprenorphine is released in thefirst 24 hours after subcutaneous administration of the solution. Theinitial burst is minimised when the solution comprises a solution ofbuprenorphine in the free base form.

As will be recognized, the upper limit of the buprenorphine which may bepresent in the solution is limited by the solubility of thebuprenorphine in the particular biocompatible solvent(s), and otheroptional components of the solution, for example the glycol and/orwater. As illustrated in the Examples, the free base form of thebuprenorphine has a higher solubility in the biocompatible organicsolvent(s) than the hydrochloride salt of buprenorphine. Accordingly, inparticular embodiments the solution comprises a solution ofbuprenorphine in the form of the free base dissolved in biocompatiblesolvent(s), and other optional components of the solution. Additionally,temperature will affect the upper solubility limit of buprenorphinedissolved in the solution. In some embodiments the upper limit ofbuprenorphine present in the solution is, for example, the solubilitylimit at room temperature (20 to 22° C., particularly at about 21° C.).The high solubility of the free base form of buprenorphine in thebiocompatible organic solvent(s) enables high concentrationbuprenorphine solutions to be prepared. A high concentration ofbuprenorphine in the solution enables a high dose of buprenorphine to beadministered in a relatively small injection volume.

When the buprenorphine is in the free base form the solution suitablycomprises for example, up to 15 wt %, up to 20 wt %, up to 25 wt %, upto 30 wt %, up to 35 wt %, up to 40 wt %, up to 45 wt %, up to 50 wt %,up to 55 wt % or up to 60 wt % of buprenorphine.

When the buprenorphine is in the form of a salt, for example ahydrochloride salt of buprenorphine, the solution suitably comprises,for example up to 11 wt %, up to 12 wt %, up to 13 wt %, up to 14 wt %,up to 15 wt %, up to 16 wt %, up to 17 wt %, up to 18 wt % or up to 19wt % of the buprenorphine.

One aspect of the invention provides a composition comprising a solutionof 5 wt % to 55 wt % buprenorphine dissolved in a biocompatible organicsolvent, wherein the composition does not comprise a biodegradablepolymer. In one embodiment, the biocompatible solvent is NMP, DMAC,DMSO, or a combination of two or more thereof. In one embodiment, thesolution can comprise from 10 wt % to 55 wt % buprenorphine. In oneembodiment, the solution can comprise from 10 wt % to 50 wt %buprenorphine. In one embodiment, the solution can comprise 15 wt % to50 wt % buprenorphine. In one embodiment, the solution can comprise 20wt % to 45 wt % buprenorphine. In one embodiment, the solution cancomprise from 20 wt % to 40 wt % buprenorphine. In one embodiment, thesolution can comprise 25 wt % to 45 wt % buprenorphine. In oneembodiment, the solution can comprise 30 wt % to 40 wt % buprenorphine.In another embodiment the solution comprises about 20 wt %, about 25 wt%, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt %, about 50wt % or about 55 wt % buprenorphine. The buprenorphine can be present inthe form of a free base (unprotonated) or a pharmaceutically acceptablesalt (e.g., HCl). In one embodiment, the buprenorphine is in the form ofa free base. In another embodiment the buprenorphine is in the form of apharmaceutically acceptable salt (e.g., HCl).

In certain embodiments the biocompatible organic solvent isN-methyl-2-pyrrolidone.

In certain embodiments the biocompatible organic solvent is dimethylacetamide.

In certain embodiments the biocompatible organic solvent is dimethylsulfoxide.

With respect to dosage, the solution can comprise up to 500 mgbuprenorphine, for example from 1 mg to 500 mg of buprenorphine. In oneembodiment, the solution can comprise from 10 mg to 350 mg ofbuprenorphine. In one embodiment, the solution can comprise from 150 mgto 300 mg of buprenorphine. In one embodiment, the solution can comprisefrom 10 mg to 50 mg buprenorphine.

In other embodiments, the composition can comprise up to 500 mgbuprenorphine in a 1 cc volume of injection, for example from 1 mg to500 mg buprenorphine in a 1 cc volume of injection. The composition cancomprise from up to 350 mg buprenorphine in a 1 cc volume of injection,for example from 10 mg to 350 mg buprenorphine in a 1 cc volume ofinjection. The composition can comprise 150 mg to 300 mg ofbuprenorphine in 1 cc or less volume of injection. The composition cancomprise 10 mg to 50 mg buprenorphine in 0.2 cc or less volume ofinjection.

The solution can optionally further comprise up to 10% by weight water,for example up to 8%, up to 6%, up to 4% or up to 2% by weight water.Suitably the solution may comprise from about 0.01% by weight to about10% by weight of water. The addition of water may reduce localirritations caused by the biocompatible organic solvent. Solutionscomprising, for example, up to 10% by weight water are suitable when thesolution is a solution of the free base form of buprenorphine.

When the solution is a solution of a salt of buprenorphine in thebiocompatible solvent(s) and optional other components, the solution mayoptionally contain higher amounts of water, for example the solution mayfurther comprise up to 20% by weight of water. Accordingly, thesolutions comprising a solution of a salt of buprenorphine, for examplea HCl salt, may further comprise up to 18%, up to 16%, up to 14% or upto 12%, up to 10% up to 8%, up to 6%, up to 4% or up to 2% by weightwater.

In another embodiment the solution does not comprise water.

In other embodiments, the solution may further comprise a glycol up to70% by weight, for example in an amount from 5% to 70% by weight of thesolvent mixture. The glycol may also reduce local irritations of thebiocompatible organic solvent (for example NMP). In other embodiments,the glycol can be present in an amount from 10% to 60% by weight of thesolvent mixture. In other embodiments, the glycol can be present in anamount from 15% to 50% by weight of the solvent mixture. In otherembodiments, the glycol can be present in an amount from 20% to 60% byweight of the solvent mixture; or from 20% to 50% by weight of thesolvent mixture. In other embodiments, the glycol can be present in anamount from 20% to 40% by weight of the solvent mixture. In otherembodiments, the glycol can be present in an amount from 20% to 30% byweight of the solvent mixture. It is to be understood that references tothe “% glycol by weight of the solvent mixture” means the % by weight ofthe glycol present in the mixture of the biocompatible organicsolvent(s) (ii), and the glycol present in the solution.

In one embodiment, the solvent mixture comprises from 90 wt % to 50 wt %of a biocompatible organic solvent and from 10 wt % to 50 wt % of aglycol. In one embodiment, the solvent mixture comprises from 80 wt % to50 wt % of a biocompatible organic solvent and from 20 wt % to 50 wt %of a glycol. In one embodiment, the solvent mixture comprises from 70 wt% to 50 wt % of a biocompatible organic solvent and from 30 wt % to 50wt % of a glycol.

The glycol can be polyethylene glycol (PEG), propylene glycol, or acombination thereof. In one embodiment, the glycol is a polyethyleneglycol having an average molecular weight from about 100 to about 1,000.In one embodiment, the glycol is a polyethylene glycol having an averagemolecular weight from about 100 to about 800. In one embodiment, theglycol is a polyethylene glycol having an average molecular weight fromabout 200 to about 500. In one embodiment, the glycol is a polyethyleneglycol having an average molecular weight from about 250 to about 450.In one embodiment, the polyethylene glycol is PEG300, PEG 400, or acombination thereof, both of which are commercially available from,e.g., Sigma-Aldrich or the Dow Chemical Company. In one embodiment, theglycol is PEG300, PEG400, propylene glycol, or a combination of two ormore thereof. In one embodiment, the glycol is PEG300. In oneembodiment, the glycol is PEG400. In one embodiment, the glycol is acombination of PEG300 and PEG400. In one embodiment, the glycol ispropylene glycol.

The term “PEG300” refers to polyethylene glycol having an averagemolecular weight from about 280 to about 320. The term “PEG400” refersto polyethylene glycol having an average molecular weight from about 380to about 420. The term “propylene glycol” refers to the compoundCH₃CH(OH)CH₂OH having a molecular weight of about 76.

The ratio of biocompatible organic solvent to glycol can be from 0.4:1to 4:1. In one embodiment, the ratio is from 0.65:1 to 2.5:1. In oneembodiment, the ratio is from 1:1 to 1.5:1.

The ratio of buprenorphine to glycol can be from 0.15:1 to 5:1. In oneembodiment, the ratio is from 0.4:1 to 3.5:1. In one embodiment, theratio is from 0.5:1 to 1:1.

In one embodiment, the composition comprises buprenorphine, abiocompatible organic solvent selected from one or more of NMP, DMAC,and DMSO; and a glycol selected from polyethylene glycol (e.g., PEG300,PEG400), propylene glycol or a combination thereof where the ratio ofbiocompatible organic solvent to glycol is from 1:3:7 to 1:0.5:0.1. Inone embodiment, the ratio of buprenorphine to biocompatible organicsolvent to glycol is from 1:2.7:6.3 to 1:0.74:0.08. In one embodiment,the ratio of buprenorphine to biocompatible organic solvent to glycol isfrom 1:2:2 to 1:1:0.4. In other embodiments, the ratio of buprenorphineto biocompatible organic solvent to glycol is 1:2.7:6.3, 1:1.5:1.5,1:1.4:0.93, 1:1.05:0.45, or 1:0.8:0.2. In another embodiment, the ratioof buprenorphine to biocompatible organic solvent to glycol is1:0.74:0.08.

In any of the embodiments described herein relating to solutionscomprising biocompatible organic solvent and a glycol, the organicsolvent may be for example NMP and the glycol may be for examplepropylene glycol.

In any of the embodiments described herein relating to solutionscomprising biocompatible organic solvent and a glycol, the organicsolvent may be for example NMP and the glycol may be for example PEG300.

In any of the embodiments described herein relating to solutionscomprising biocompatible organic solvent and a glycol, the organicsolvent may be for example NMP and the glycol may be for example PEG400.

Suitably the only solvent(s) present in the solution are thebiocompatible organic solvent(s); optionally a glycol and optionallywater. Accordingly in one embodiment the solution does not contain anyorganic solvents other than N-methyl-2-pyrrolidone, dimethyl acetamide,dimethyl sulfoxide, or a glycol, or a combination of two or morethereof. In another embodiment the solution consists of thebuprenorphine dissolved in N-methyl-2-pyrrolidone, dimethyl acetamide,dimethyl sulfoxide, optionally a glycol and optionally water, or acombination of two or more thereof. In another embodiment the solutionconsists of the buprenorphine dissolved in N-methyl-2-pyrrolidone,dimethyl acetamide, dimethyl sulfoxide and optionally a glycol, or acombination of two or more thereof. In another embodiment the solutionconsists of the buprenorphine dissolved in N-methyl-2-pyrrolidone,dimethyl acetamide, or dimethyl sulfoxide, or a combination of two ormore thereof. In these embodiments the concentration of buprenorphine,solvents(s), optional glycol and optional water, may be any of thevalues disclosed herein.

The compositions described herein can optionally further comprise one ormore pharmaceutically acceptable antioxidants. The antioxidant may beascorbic acid, vitamin E, butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), ethylenediaminetetraacetic acid (EDTA), or acombination thereof. In one embodiment, the antioxidant is ascorbicacid, vitamin E, BHT, BHA, or a combination thereof. The antioxidant maybe present in an amount from about 0.01 wt % to about 10 wt %, or fromabout 0.1 wt % to about 5 wt %, or from about 0.1 wt % to about 3 wt %.The antioxidant may enhance the stability of buprenorphine.

In one embodiment, the composition can consist essentially ofbuprenorphine, NMP, and PEG400, which are present in a ratio from 1:3:7to 1:0.5:0.1. In one embodiment, the ratio can be from 1:2.7:6.3 to1:0.74:0.08. In one embodiment, the ratio can be from 1:2:2 to 1:1:0.4.In other embodiments, the ratio can be 1:2.7:6.3, 1:1.5:1.5, 1:1.4:0.93,1:1.05:0.45, 1:0.8:0.2 or 1:0.74:0.08.

In one embodiment, the composition can consist of buprenorphine, NMP,and PEG400, which are present in a ratio of from 1:3:7 to 1:0.5:0.1. Inone embodiment, the ratio can be from 1:2.7:6.3 to 1:0.74:0.08. In otherembodiments, the compounds are present in a ratio of from 1:2:2 to1:1:0.4. In other embodiments, the ratio is 1:2.7:6.3, 1:1.5:1.5,1:1.4:0.93, 1:1.05:0.45, or 1:0.8:0.2 or 1:0.74:0.08.

In one embodiment, the composition can consist essentially ofbuprenorphine, NMP, and PEG300, which are present in a ratio from 1:3:7to 1:0.5:0.1. In one embodiment, the ratio can be from 1:2.7:6.3 to1:0.74:0.08. In one embodiment, the ratio can be from 1:2:2 to 1:1:0.4.In other embodiments, the ratio can be 1:2.7:6.3, 1:1.5:1.5, 1:1.4:0.93,1:1.05:0.45, 1:0.8:0.2 or 1:0.74:0.08.

In one embodiment, the composition can consist of buprenorphine, NMP,and PEG300, which are present in a ratio of from 1:3:7 to 1:0.5:0.1. Inone embodiment, the ratio can be from 1:2.7:6.3 to 1:0.74:0.08. In otherembodiments, the compounds are present in a ratio of from 1:2:2 to1:1:0.4. In other embodiments, the ratio is 1:2.7:6.3, 1:1.5:1.5,1:1.4:0.93, 1:1.05:0.45, 1:0.8:0.2 or 1:0.74:0.08.

In other embodiments, the composition can consist of about 40%buprenorphine in NMP. In other embodiments, the composition can consistof about 15% to about 35% buprenorphine in a solution containing NMP andPEG400, where the NMP and PEG400 are present in a ratio ranging from40:60 to 70:30, preferably in a ratio from 50:50 to 60:40. In oneembodiment, the composition can consist of about 30% buprenorphine in a60:40 NMP/PEG400 solution. In another embodiment, the composition canconsist of about 20% buprenorphine in a 50:50 NMP/PEG400 solution. Inother embodiments, the composition can consist of about 15% to about 35%buprenorphine in a solution containing NMP and PEG300 in a ratio rangingfrom 40:60 to 70:30, preferably in a ratio from 50:50 to 60:40. In oneembodiment, the composition can consist of about 20% buprenorphine in a50:50 NMP/PEG300 solution. In another embodiment, the composition canconsist of about 30% buprenorphine in a 60:40 NMP/PEG300 solution.

In other embodiments the composition can consist of about 300 mg ofbuprenorphine in about 450 mg NMP. In other embodiments, the compositioncan consist of about 300 mg of buprenorphine in about 700 mg of a 60:40NMP/PEG400 solution. In other embodiments, the composition can consistof about 150 mg of buprenorphine in about 600 mg of a 50:50 NMP/PEG400solution. In other embodiments, the composition can consist of about 20mg of buprenorphine in about 80 mg of a 50:50 NMP/PEG400 solution. Inother embodiments, the composition can consist of about 50 mg ofbuprenorphine in about 117 mg of a 60:40 NMP/PEG400 solution.

Unless specified otherwise, reference herein to a % of a particularcomponent is a reference to a % by weight.

According to a further aspect of the invention there is provided acomposition described herein for use as a medicament.

According to a further aspect of the invention there is provided acomposition described herein for use in the treatment of opioiddependence or pain.

According to a further aspect of the invention there is provided the useof a composition described herein in the manufacture of a medicament forthe treatment of opioid dependence or pain.

According to another aspect of the invention, there is provided a methodof treating a patient for opioid dependence or pain comprisingsubcutaneously administering to the patient a therapeutically effectiveamount of any of the compositions described herein.

According to another aspect of the invention there is provided acomposition as described herein for use in treating a patient for opioiddependence or pain, wherein the composition is administered to thepatient subcutaneously.

According to another aspect of the invention there is provided the useof a composition as described herein for the manufacture of a medicamentfor treating a patient for opioid dependence or pain, wherein thecomposition is administered to the patient subcutaneously.

In one embodiment the compositions for use, use of the compositions andmethods described herein are for the treatment of pain.

In one embodiment the compositions for use, use of the compositions andmethods described herein are for the treatment of opioid dependence.

Preferably, the compositions for use, use of the compositions andmethods described herein provide treatment for opioid dependence or painby subcutaneously administering a therapeutically effective amount ofany of the compositions described herein once per month. The term“month” refers to a period of time from 28 days to 31 days. In oneembodiment, a month is 30 days. In other embodiments, the compositionsare subcutaneously administered to the patient once every three months.

Typically, the “therapeutically effective amount” refers tobuprenorphine in an amount from about 0.10 milligrams (mg) to about 10mg per day. The methods of administration can provide a therapeuticallyeffective level of buprenorphine within about one day afteradministration of the composition. The compositions described herein mayprovide therapeutically effective levels of buprenorphine for about onemonth to about three months after administration.

Preparation of Composition

The present invention provides a method of manufacturing a composition,suitably as defined herein. The method suitably comprises mixingtogether, in any particular order deemed appropriate, any relevantcomponents required to form a composition as defined herein. The skilledperson may refer to the Examples or techniques well known in the art forforming pharmaceutical solution compositions. Different embodiments willsuitably require different combinations of components to be mixed,potentially in different amounts. The skilled person can readily deducesuch combinations and amounts by reference to the foregoing disclosurerelating to the composition.

Suitably the method involves mixing together the relevant components,suitably so that all of the components are (substantially or entirely)dissolved in the biocompatible organic solvent. Suitably the solution isprepared at room temperature. Alternatively the mixture may be heatedgently to for example 30 to 40° C. to aid dissolution of thebuprenorphine in the biocompatible organic solvent(s) and othercomponents.

The method may involve first preparing a one or more pre-mixtures (orpre-solutions) of each, some or all components, before saidpre-mixture(s) or pre-solution(s) are then mixed together, optionallyalong with any components not provided as a pre-mixture or pre-solutionto ultimately form the solution.

The buprenorphine present in the solutions described herein is dissolvedin the solution. Preferably all of the buprenorphine is dissolved in thesolution. However, in some embodiments the solution may comprise smallamounts of buprenorphine which is not dissolved, for example less than 5wt %, less than 1 wt % or less than 0.1 wt % may be present as solids,although this is not preferred. Accordingly, if the solution containssolid buprenorphine the solids are preferably removed prior to use ofthe solution by for example filtration.

The final composition may be filtered, suitably to remove particulatematter. Suitably filtration is through filters sized at or below 1 μm,suitably at 0.24 μm. Suitably, filtration is through either PES filtersor PVDF filters, suitably with 0.22 μm PES filters.

The solutions described herein are preferably prepared as a sterilesolution. Methods for preparing sterile pharmaceutical solutions arewell known and include for example preparing the solution from sterilecomponents under aseptic processing conditions or by sterile filtrationof the solution. Accordingly in a further embodiment there is providedany of the solutions described herein in a sterile form. The solutionsare suitably pyrogen free. Generally a pyrogen free solution may beprepared using pyrogen-free starting materials and pyrogen free reactionvessels/processing equipment. Accordingly, particular solutions arethose which are sterile and pyrogen free.

Package or Medical Device

The compositions of the invention may be incorporated into a package ormedical device, for example, comprising a sterile container pre-filledor to be filled with a composition as defined herein. The presentinvention therefore provides a package or medical device, comprising asterile container pre-filled or configured for filling with acomposition as defined herein. The sterile container is suitablypyrogen-free.

The sterile container is suitably selected from a syringe, dispenser,cartridge, vial, ampoule, bottle or self-injection pen.

In some embodiments, the device or package may be filled immediatelyprior to use with the composition. In some embodiments, the compositionmay be provided within the device or package, for example as apre-filled syringe.

Kit of Parts

The present invention provides a kit of parts comprising a medicaldevice (without the composition incorporated therein), a composition asdefined herein (optionally contained in a separate package orcontainer), and optionally a set of instructions with directionsregarding the administration (e.g. subcutaneous administration of thecomposition. The user may then fill the medical device with thecomposition (which may be provided in a vial or ampoule or such like)prior to administration

The compositions described herein are suitably prepared as a medicinalproduct comprising a container and the composition.

EXAMPLES

The following examples are for illustrative purposes and are notintended to limit the scope of the disclosure.

All rat preclinical studies were conducted in male Sprague-Dawley rats.Five rats per Test Article per time point were injected subcutaneouslyunder full anesthesia in the dorsal thoracic (DT) region withapproximately 100 mg of the Test Article, described below. During thecourse of the study, the animals were observed for overt toxicity andany existing test site abnormalities, including redness, bleeding,swelling, discharge, bruising and Test Article extrusion at theinjection site were observed and recorded. In addition, injectionweights were recorded at administration and body weights were taken andrecorded at administration and at termination. At selected time points,five rats per Test Article were anesthetized and bled (about 5 mL) viacardiac puncture. Blood was collected in labeled potassium EDTA tubes.The blood was centrifuged for 10 min at 3000 rpm. The plasma fractionwas transferred to a labeled 5 mL plastic culture tube and stored at −20degrees C. Rat plasma samples were analyzed for buprenorphineconcentration using a procedure described below. After blood collection,the rat was sacrificed in a carbon dioxide chamber. The injection sitewas cut open and the drug residue and the surrounding tissues werecarefully removed and placed in a scintillation vial. The vials werestored at −20 degrees C. until analysis. The retrieved drugresidue/tissue was analyzed for buprenorphine content using thebuprenorphine analysis method described below.

Buprenorphine Analysis in Rat Plasma Samples: This procedure was basedon the method described by Li-Heng Pao et al., Journal of ChromatographyB, 746:241-247 (2000). High Performance Liquid Chromatography had thefollowing conditions: Mobile Phase: 80/20 acetonitrile/5 mM sodiumacetate buffer (pH 3.75); flow rate: 1.2 mL/min; autosamplertemperature: room temperature; column temperature: 25° C.; detection:fluorescence (excitation at 215 nm and emission at 355 nm); total runtime: 12 min; injection volume: 50 μL; column: Phenomenex Luna Silica(2) 250×4.6 mm, 5 μm; column storage: 100% acetonitrile; approximateretention time for buprenorphine and the internal standard: 7.3 min and7.9 min.

Buprenorphine Extraction/Analysis Procedure: To the vials containing theretrieved drug residue/tissue, 10 mL of the formulation dissolutionsolution [90/5/5 acetonitrile/glacial acetic acid/water] was added. Thevials were then shaken at 200 rpm at room temperature on an orbitalshaker for at least 2 hours. The vials were then centrifuged at 2500 rpmfor 10 minutes. After centrifuge, the vials were removed from thecentrifuge. A portion of the supernatant from the vial was transferredinto a HPLC vial and if necessary, the transferred solution in the vialwas further diluted using the formulation dissolution solution to asuitable concentration for HPLC analysis.

The High Performance Liquid Chromatography had the following conditions:Mobile Phase A: 0.065% sodium octanesulfonic acid and 0.1%trifluoroacetic acid in water; Mobile Phase B: 90/10 acetonitrile/0.065%sodium octanesulfonic acid and 0.1% trifluoroacetic acid in water; flowrate: 1.0 ml/min; autosampler temperature: room temperature; columntemperature: 30° C.; detection: 285 run (UV); total run time: 21 min;injection volume: 20 μL; column: Phenomenex Luna C18 250×4.6 mm, 5 μm;column storage: 70/30 acetonitrile/water; each sample run according tothe following gradient program:

Time (Minute) Mobile Phase A Mobile Phase B 0 100% 0% 2 100% 0% 16  20%80% 18  0% 100% 20 100% 0% 21 100% 0%As can be seen from the table above, buprenorphine had an approximateretention time of 16.8 minutes.

Preparation of standard solutions was conducted as follows: standardstock solution was made by dissolving approximately 10 mg buprenorphinein 10 mL 0.2% acetic acid aqueous solution. A series standards rangingfrom 40 ppm to 500 ppm were prepared by diluting proper amount of thestandard stock solution in HPLC vials with water.

The dog study was conducted in male beagles with body weight in therange of 8-12 kg. Six dogs per group were injected subcutaneously in thedorsal thoracic region at a buprenorphine equivalent dose of 10 mg to 60mg per dog, depending on the study design. Exact injection doses wereobtained by weighing the injection syringe before and after eachinjection. After injection, the dogs were bled periodically via jugularvein into EDTA tubes. Plasma samples were then derived and stored in a−20° C. freezer until analysis. Dogs were weighed once daily on bloodcollection time points. The test sites were evaluated for anyabnormalities including redness, bleeding, swelling, discharge,bruising, and TA extrusion on blood collection days. Dogs were alsoobserved post-administration for signs of overt toxicity throughout theentire study period.

Buprenorphine Analysis in Dog Plasma Samples: Plasma samples from dogstudies were analyzed for buprenorphine and norbuprenorphine levelsusing a liquid-liquid extraction step followed by LC-MS-MS analysis.

Example 1: Measurement of Buprenorphine Solubility in BiocompatibleSolvents

Excess amount of buprenorphine or buprenorphine hydrochloride wasweighed into a 1.8 cc HPLC vial containing about 0.5 g selected solvent.The vial was capped and placed on a jar mill rotating at 100 rpm at roomtemperature overnight. It was then centrifuged and part of top clearsolution was weighed out and diluted in 1% acetic acid aqueous solution.Buprenorphine content in the solution was measured using the HPLC methoddescribed above.

TABLE 1 Buprenorphine Solubility in Various Solvents and SolventMixtures Solvent/Solvent Mixture Buprenorphine Solubility (%, w/w) NMP60.9 DMSO 55.0 DMAC 61.5 80/20 NMP/Propylene glycol (w/w) 45.5 70/30NMP/Propylene glycol (w/w) 35.9 60/40 NMP/Propylene glycol (w/w) 24.750/50 NMP/Propylene glycol (w/w) 14.3 80/20 NMP/PEG400 (w/w) 55.0 70/30NMP/PEG400 (w/w) 47.3 60/40 NMP/PEG400 (w/w) 39.8 50/50 NMP/PEG400 (w/w)30.7 40/60 NMP/PEG400 (w/w) 20.6 30/70 NMP/PEG400 (w/w) 12.4 20/80NMP/PEG400 (w/w) 6.6 80/20 NMP/PEG300 (w/w) 52.1 70/30 NMP/PEG300 (w/w)45.9 60/40 NMP/PEG300 (w/w) 37.4 50/50 NMP/PEG300 (w/w) 28.2 40/60NMP/PEG300 (w/w) 18.8 30/70 NMP/PEG300 (w/w) 10.9 20/80 NMP/PEG300 (w/w)5.9 80/20 NMP/water (w/w) 6.2

TABLE 2 Buprenorphine Hydrochloride Solubility in Various Solvents andSolvent Mixture Solvent/Solvent Mixture Buprenorphine HCl Solubility (%,w/w) NMP 17.9 DMSO 19.7 DMAC 11.3 80/20 NMP/water (w/w) 14.9

Tables 1 and 2 show that a solution containing more than 50%buprenorphine (w/w) can be prepared at room temperature using NMP, DMSO,or DMAC as the solvent. Even buprenorphine hydrochloride solution can beprepared at more than 10% by weight in NMP, DMSO, or DMAC.

Example 2: Preparation of 20 wt % and 40 wt % Buprenorphine Solutions inNMP

0.630 g and 0.840 g buprenorphine free base were weighed into twoseparate 1-drum vials. 2.520 g and 1.260 g NMP were then added to eachvial accordingly. The vials were shaken and vortexed until completedissolution of the drug. Each solution was then loaded into a 3 ccsyringe and a sterile 0.2μ PTFE syringe tip filter was attached to thesyringe. The solution was then filtered and the filtrate was filled intoseveral 1 cc glass ampoules. The ampoules were then hermetically sealedwith an open flame.

Example 3: Initial Burst Studies in Rats

In the first rat study, seven NMP solutions at buprenorphineconcentrations ranging from 1% to 40% were injected subcutaneously inthe DT region of the rats. At 24 hours, the rats were anesthetized andblood samples (about 5 mL) were taken via cardiac puncture. The ratswere then sacrificed and the drug residues in each rat were removed.Both plasma and drug residue samples were analyzed for buprenorphinecontent. Results are shown in Tables 3 and 4.

TABLE 3 Percent of Buprenorphine Released at 24 Hours (Initial Burst) inRats Buprenorphine Solution Initial Burst (%) 1% in NMP 80.1 ± 6.0  3%in NMP 38.7 ± 17.0 5% in NMP 29.9 ± 18.0 10% in NMP 22.1 ± 16.2 20% inNMP 6.7 ± 2.8 30% in NMP 4.8 ± 6.5 40% in NMP 0.9 ± 2.0

TABLE 4 Buprenorphine Plasma Levels at 24 Hours Buprenorphine SolutionPlasma Level (ng/mL) 1% in NMP  6.1 ± 2.5 3% in NMP  8.0 ± 2.6 5% in NMP10.6 ± 2.0 10% in NMP  9.6 ± 2.1 20% in NMP 15.8 ± 6.6 30% in NMP 13.0 ±3.3 40% in NMP 12.4 ± 3.1

In the second rat study, six buprenorphine solutions in various solventsor solvent mixtures were investigated in a similar 24-hour rat study asthe first rat study. Results are shown in Tables 5 and 6.

TABLE 5 Percent of Buprenorphine Released at 24 Hours (Initial Burst) inRats Buprenorphine Solution Initial Burst (%) 50% in NMP 4.4 ± 1.1 20%in DMSO 9.7 ± 2.8 20% in DMAC 8.2 ± 3.6 20% in 80/20 NMP/propyleneglycol 8.9 ± 2.5 20% in 80/20 NMP/PEG400 6.9 ± 1.3 20% in 91/9 NMP/water6.5 ± 2.9

TABLE 6 Buprenorphine Plasma Levels at 24 Hours Buprenorphine SolutionPlasma Level (ng/mL) 50% in NMP 21.9 ± 3.3 20% in DMSO 20.0 ± 6.1 20% inDMAC 23.6 ± 5.5 20% in 80/20 NMP/propylene glycol 17.0 ± 0.6 20% in80/20 NMP/PEG400 17.7 ± 3.9 20% in 91/9 NMP/water 17.2 ± 4.3 40% in NMP12.4 ± 3.1

The above results indicate that buprenorphine initial burst is highlydependent on buprenorphine content of the solution. Initial burst waslarge when buprenorphine concentration was below 5%. However, whenbuprenorphine concentration is 20% or higher, initial burst will bebelow 10% regardless of the solvent used in preparation of thebuprenorphine solutions.

In a third burst study, four buprenorphine hydrochloride solutions wereinjected subcutaneously in rats. Initial burst results are shown inTable 7.

TABLE 7 Percent of Buprenorphine Hydrochloride Released at 24 Hours(Initial Burst) in Rats Buprenorphine HCl Solution Initial Burst (%) 10%in NMP 28.7 ± 5.0 10% in DMSO 34.3 ± 3.4 10% in DMAC 35.0 ± 6.3 10% in80/20 NMP/water 36.5 ± 6.4

Although a large portion of buprenorphine hydrochloride still remains atthe injection site after 24 hours, initial bursts are higher compared tobuprenorphine solutions.

Example 4: 56-Day Buprenorphine Release Study in Rats

Two solution formulations with 20% buprenorphine by weight were injectedsubcutaneously in the rats. The first formulation is a NMP solutionwhile the second formulation employed a solvent mixture of 1:1 NMP andpropylene glycol (w/w). Both plasma samples and drug residue samplesremoved from the injection sites were analyzed. Release results fromretrieved drug residues are shown in Table 8. Table 9 showsbuprenorphine plasma levels over time. The data are also depicted inFIG. 1.

TABLE 8 Percent of Buprenorphine Released Based on Retrieved DrugResidue Time 20% Buprenorphine in (Days) 20% Buprenorphine in NMP 1:1NMP/Propylene Glycol 1 10.2 ± 4.8  1.8 ± 1.9 7  7.7 ± 2.3  6.3 ± 6.1 1415.7 ± 4.2 20.6 ± 3.9 21 26.5 ± 6.8 27.9 ± 9.9 28 33.0 ± 7.5  32.9 ±16.8 42  62.7 ± 13.7 43.5 ± 6.5 56 68.4 ± 8.8 60.1 ± 6.2

TABLE 9 Buprenorphine Plasma Levels Time 20% Buprenorphine in 20%Buprenorphine in (Days) NMP (ng/mL) 1:1 NMP/Propylene Glycol (ng/mL) 1 29.7 ± 10.0 26.9 ± 10.4 7 17.0 ± 4.0 13.5 ± 10.2 14 19.4 ± 6.3 37.2 ±12.1 21  24.0 ± 14.1 23.5 ± 12.1 28 17.9 ± 8.9 18.1 ± 13.0 42 29.7 ± 3.620.8 ± 9.9  56 18.1 ± 4.1 24.9 ± 8.3 

Buprenorphine plasma levels were maintained steady during the entire56-day study period for both formulations. In addition, there were stillsubstantial amount of buprenorphine remaining at the injection siteafter 56 days.

Example 5: First Pharmacokinetics Study in Beagle Dogs

Two solutions with 20% and 40% buprenorphine in NMP by weight wereinjected subcutaneously in the dorsal thoracic region at a dose of 60 mgbuprenorphine per dog. Blood samples were collected periodically fromjugular vein and plasma samples were derived and kept in frozen untilanalysis. Plasma samples were analyzed for both buprenorphine andnorbuprenorphine levels using a validated LC-MS-MS method. Assay resultsare listed in Table 10 and also depicted in FIG. 2. Results show thatboth formulations were able to maintain buprenorphine plasma levelsabove 1.0 ng/mL for 31 days.

TABLE 10 Buprenorphine and Norbuprenorphine Plasma Levels (Mean ± SD)after SC Injection of Buprenorphine NMP Solutions BuprenorphineNorbuprenorphine Time (Day) (ng/mL) SD (ng/mL) SD Group I: 20%buprenorphine in NMP −1 BLQ < (0.100) N/A BLQ < (0.0800) N/A 1 hr 2.422.01 0.533 0.151 2 hr 4.23 2.70 0.511 0.164 4 hr 5.42 3.43 0.354 0.133 8hr 6.72 4.51 0.140 0.084 1 11.2 4.76 0.0722 0.0794 3 9.45 4.78 0.08700.1017 7 6.06 2.83 0.0323 0.0501 10 4.52 0.99 0.0142 0.0348 14 4.13 1.37BLQ < (0.0800) N/A 17 3.87 1.94 BLQ < (0.0800) N/A 21 2.84 1.58 BLQ <(0.0800) N/A 24 1.93 0.87 BLQ < (0.0800) N/A 28 1.24 0.41 BLQ < (0.0800)N/A 31 1.04 0.40 BLQ < (0.0800) N/A 38 0.668 0.324 BLQ < (0.0800) N/A 450.418 0.260 BLQ < (0.0800) N/A 52 0.318 0.242 BLQ < (0.0800) N/A 660.198 0.177 BLQ < (0.0800) N/A 80 0.0693 0.0847 BLQ < (0.0800) N/A 940.0208 0.0510 BLQ < (0.0800) N/A 122 BLQ < (0.100) N/A BLQ < (0.0800)N/A 150 0.0202 0.0494 BLQ < (0.0800) N/A 178 BLQ < (0.100) N/A BLQ <(0.0800) N/A Group II: 40% buprenorphine in NMP −1 BLQ < (0.100) N/A BLQ< (0.0800) N/A 1 hr 1.25 0.46 0.253 0.149 2 hr 2.60 0.95 0.227 0.139 4hr 3.06 1.16 0.136 0.094 8 hr 3.50 1.53 0.0326 0.0506 1 7.63 3.61 0.01670.0408 3 5.65 2.20 0.0530 0.0849 7 3.60 1.83 BLQ < (0.0800) N/A 10 3.011.09 0.0182 0.0445 14 2.96 1.39 BLQ < (0.0800) N/A 17 3.62 3.15 BLQ <(0.0800) N/A 21 2.93 2.72 BLQ < (0.0800) N/A 24 2.08 1.42 BLQ < (0.0800)N/A 28 1.61 0.92 BLQ < (0.0800) N/A 31 1.32 0.70 BLQ < (0.0800) N/A 380.958 0.382 BLQ < (0.0800) N/A 45 0.749 0.267 BLQ < (0.0800) N/A 520.668 0.180 BLQ < (0.0800) N/A 66 0.508 0.171 BLQ < (0.0800) N/A 800.412 0.225 BLQ < (0.0800) N/A 94 0.359 0.175 BLQ < (0.0800) N/A 1220.207 0.122 BLQ < (0.0800) N/A 150 0.176 0.100 BLQ < (0.0800) N/A 1780.136 0.076 BLQ < (0.0800) N/A

The above example shows that both NMP solutions had very low initialbursts of below 5% estimated from the ratio of area under the curve(AUC) in the initial 24 hours over total AUC up to 178 days. Theformulations yielded comparable total AUCs and there were no visiblelocal tissue reactions or systematic toxicities except the known sideeffects of buprenorphine.

Example 6: Second Pharmacokinetics Study in Beagle Dogs

A solution with 25 wt % buprenorphine in a 50/50 NMP/PEG400 solventmixture by weight was prepared by simply dissolving buprenorphine in thesolvent mixture. The solution was then sterile filtered into emptysealed sterile and pyrogen free vials. The solution was injectedsubcutaneously in the dorsal thoracic region to three groups of beaglesat 10 mg, 30 mg, and 60 mg buprenorphine per dog. Blood samples werecollected periodically from jugular vein and plasma samples were derivedand kept in frozen until analysis. Plasma samples were analyzed for bothbuprenorphine and norbuprenorphine levels using a validated LC-MS-MSmethod. Buprenorphine plasma levels are listed in Table 11 and the dataare also depicted in FIG. 3. Norbuprenorphine levels were not listedbecause the levels were very low and inconsequential. Results show thatsteady plasma buprenorphine levels were maintained for 28 days at theirrespective levels for all three groups.

TABLE 11 Buprenorphine Plasma Levels (Mean ± SD) after SC Injection ofthe Same Buprenorphine Solution at Three Different Doses in Dogs TimeGroup I Group II Group III (Day) (10 mg) SD (30 mg) SD (60 mg) SD −1 BLQ<(0.100) N/A BLQ N/A BLQ N/A <(0.100) <(0.100) 1 hr 1.13 0.89 1.30 0.804.08 3.18 2 hr 1.68 1.17 2.07 1.14 5.48 2.83 4 hr 1.73 0.80 2.55 1.145.58 2.03 8 hr 1.18 0.27 2.50 0.89 5.32 1.76 1 1.70 0.36 4.10 1.75 6.651.97 3 0.958 0.298 3.15 1.66 5.27 1.77 7 0.715 0.262 2.48 1.37 4.33 1.4410 1.17 1.17 1.99 0.70 5.00 2.27 14 1.41 0.77 3.92 2.21 10.1 6.1 17 1.400.62 4.21 2.20 7.98 4.72 20 0.983 0.570 3.17 1.81 6.54 3.74 24 0.4180.179 2.16 1.07 4.19 2.13 28 0.243 0.239 1.50 0.50 2.94 1.25 31 0.1830.241 1.03 0.27 2.24 1.01 38 0.134 0.276 0.566 0.199 1.27 0.49 45 0.08980.2200 0.436 0.309 0.839 0.265 52 0.0738 0.1809 0.309 0.296 0.586 0.28166 0.0347 0.0849 0.194 0.180 0.431 0.333 81 0.0278 0.0682 0.174 0.1870.319 0.339 94 0.0217 0.0531 0.0802 0.1292 0.229 0.273 122 BLQ <(0.100)N/A 0.0758 0.1858 0.184 0.231

Key pharmacokinetic parameters were derived for all three groups and theparameters are listed in Table 12. Notably, all three groups had a verylow initial burst that was less than 5%. Moreover, both of their initialand plateau plasma levels (Initial C_(max) and Plateau C_(max)) wereonly about twice as high as their respective average levels in 28 days(C_(Ave0-28d)) indicating very steady plasma levels over the 28 dayperiod. Most importantly, both C_(Ave0-28d) and AUC_(0-122d) values forthe three groups showed a ratio very close to the dose ratio of 1:3:6demonstrating that the increase in plasma levels was proportional toincrease in doses for this buprenorphine solution formulation.

TABLE 12 Mean (±Standard Deviation) Buprenorphine PharmacokineticParameters for Each Group Group I Group II Group III Parameters Unit (10mg) (30 mg) (60 mg) Initial t_(max) Hours 14 24 14 Initial C_(max) ng/mL2.21 ± 0.86 4.33 ± 1.57 7.18 ± 2.43 Plateau t_(max) Days 17   15.5 14Plateau C_(max) Ng/mL 2.04 ± 0.92 5.37 ± 1.92 10.5 ± 5.7  AUC_(0-1 d)ng/mL*Day 1.43 ± 0.29 2.91 ± 1.06 5.64 ± 1.72 AUC_(0-122 d) ng/mL*Day32.3 ± 7.3  81.2 ± 25.5 166 ± 69  Initial Burst % 4.7 ± 1.6 2.7 ± 0.72.6 ± 0.5 C_(Ave0-28 d) ng/mL 0.976 ± 0.262 2.90 ± 0.91 5.91 ± 2.45t_(min 1-28 d) Days 28 26 28 C_(min 1-28 d) ng/mL 0.195 ± 0.139 1.20 ±0.29 2.94 ± 1.25

With reference to Table 12, initial maximum plasma level (InitialC_(max)) is the peak plasma concentration reached for each animal withinthe first 24 hours. Initial C_(max) for each group is the averageInitial C_(max) of that group. Initial t_(max) is the time to reach theinitial peak plasma concentration for each animal and Initial t_(max)for each group is the median t_(max) for that group. Plateau maximumlevel (Plateau C_(max)) is the secondary plasma peak reached after Day 1and Plateau t_(max) is the time to reach the secondary peak plasmalevels. Area under the curve (AUC) was calculated using the trapezoidalmethod. Initial burst in the first 24 hours is the ratio of AUC_(0-1d)over AUC_(0-122d). Average plasma level in the first 28 days(C_(Ave0-28d)) was calculated using AUC_(0-28d) divided by 28 days.C_(min1d-28d) is the lowest plasma level from Day 1 to Day 28 afterinjection. C_(min1d-28d) for each group is the average C_(min1d-28d) ofthat group. The t_(min1d-28d) is the time to reach the lowest plasmalevel during the Day 1 to Day 28 period and t_(min1d-28d) for each groupis the median t_(min1d-28d) of that group.

Example 7: Third Pharmacokinetics Study in Beagle Dogs

Three buprenorphine solution formulations were prepared in sterile andpyrogen free vials after sterile filtration. The three formulations hadthe following composition: (1) 50 wt % buprenorphine in NMP; (2) 50 wt %buprenorphine in 80/20 NMP/PEG400 (w/w); and (3) 40 wt % buprenorphinein 70/30 NMP/PEG300 (w/w). All three solutions were injectedsubcutaneously in the dorsal thoracic region to three separate groups ofbeagles at the same dose of 60 mg buprenorphine per dog. Blood sampleswere collected periodically from jugular vein and plasma samples werederived and kept in frozen until analysis. Plasma samples were analyzedfor both buprenorphine and norbuprenorphine levels using a validatedLC-MS-MS method. Buprenorphine plasma levels are listed in Table 13 andthe data are also depicted in FIG. 4. Norbuprenorphine levels were notlisted because the levels were very low and inconsequential. Resultsshow that all three formulations yielded similar plasma profiles. TheirPK parameters (see Table 14) also show these formulations had verysimilar performances in dogs. All three solution formulations yieldedvery steady plasma levels with their ratios of C_(max) over C_(min1-28d)smaller than 4 and their C_(min1-28d) above 1.0 ng/mL. Theseformulations also produced very low initial bursts of less than 3%.

TABLE 13 Buprenorphine Plasma Levels (Mean ± SD) after SC Injection ofThree Buprenorphine Solutions at the Same Dose of 60 mg Buprenorphine inDogs Group I Group II Group III Time (50% in (50% in 80/20 (40% in 70/30(Day) NMP) SD NMP/PEG400) SD NMP/PEG300) SD −1 BLQ <(0.100) N/A BLQ<(0.100) N/A BLQ <(0.100) N/A 1 hr 0.945 0.797 2.78 4.12 1.78 1.19 2 hr1.80 1.10 3.45 3.19 2.85 1.07 4 hr 3.12 2.26 3.12 1.92 3.73 1.09 8 hr3.52 2.63 2.19 1.06 3.40 1.57 1 3.31 1.10 2.72 1.56 4.30 1.89 3 3.581.83 2.25 0.59 3.85 1.47 7 1.96 0.78 1.55 0.51 2.47 0.97 10 1.63 0.561.34 0.49 2.05 0.47 14 2.05 0.81 2.06 1.07 2.63 1.19 17 2.80 1.32 2.861.05 3.93 1.38 20 4.01 2.43 2.92 1.55 4.28 2.54 24 3.67 2.80 2.32 1.312.99 1.74 28 2.27 1.25 1.67 0.95 1.67 0.82 31 2.04 1.14 1.55 1.04 1.470.75 38 1.37 0.72 1.13 0.64 0.948 0.420 45 1.08 0.54 0.879 0.324 0.7080.312 52 0.911 0.498 0.689 0.164 0.561 0.238 66 0.581 0.242 0.463 0.1050.348 0.140 79 0.387 0.173 0.321 0.065 0.313 0.300 94 0.2848 0.13720.2457 0.0680 0.1650 0.0869 122 0.1478 0.1283 0.1565 0.1239 0.12530.0645 150 0.0978 0.1146 0.1367 0.1114 0.1230 0.0693 178 0.0568 0.08800.1198 0.0947 0.0453 0.0710

TABLE 14 Mean (±Standard Deviation) Buprenorphine PharmacokineticParameters Group II Group III Group I (50% in (40% in (50% in 80/20 NMP/70/30 NMP/ Parameters Unit NMP) PEG400) PEG300) Initial t_(max) Hours  1  0.58 1  Initial C_(max) ng/mL 4.22 ± 2.28 4.78 ± 3.43 4.62 ± 1.60Plateau t_(max) Days 20 18.5 18.5 Plateau C_(max) Ng/mL 5.16 ± 2.51 3.61± 1.09 5.47 ± 1.39 AUC_(0-1 d) ng/mL*Day 3.11 ± 1.73 2.54 ± 1.26 3.56 ±1.36 AUC_(0-178 d) ng/mL*Day 146 ± 49  118 ± 24  134 ± 34  Initial Burst% 2.1 ± 1.0 2.1 ± 0.9 2.7 ± 0.9 C_(Ave0-28 d) ng/mL 2.80 ± 1.23 2.17 ±0.81 3.09 ± 0.83 t_(min 1-28 d) Days 10 21   28   C_(min 1-28 d) ng/mL1.36 ± 0.61 1.21 ± 0.48 1.41 ± 0.52

With reference to Table 14, initial maximum plasma level (InitialC_(max)) is the peak plasma concentration reached for each animal withinthe first 24 hours. Initial C_(max) for each group is the averageInitial C_(max) of that group. Initial t_(max) is the time to reach theinitial peak plasma concentration for each animal and Initial t_(max)for each group is the median t_(max) for that group. Plateau maximumlevel (Plateau C_(max)) is the secondary plasma peak reached after Day 1and Plateau t_(max) is the time to reach the secondary peak plasmalevels. Area under the curve (AUC) was calculated using the trapezoidalmethod. Initial burst in the first 24 hours is the ratio of AUC_(0-1d)over AUC_(0-178d). Average plasma level in the first 28 days(C_(Ave0-28d)) was calculated using AUC_(0-28d) divided by 28 days.C_(min1d-28d) is the lowest plasma level from Day 1 to Day 28 afterinjection. C_(min1d-28d) for each group is the average C_(min1d-28d) ofthat group. The t_(min1d-28d) is the time to reach the lowest plasmalevel during the Day 1 to Day 28 period and t_(min1d-28d) for each groupis the median t_(min1d-28d) of that group.

The present invention also realizes the benefit of a small injectionvolume by utilizing the exceptionally high buprenorphine solubility ofmore than 50% in NMP, DMAC, or DMSO.

Without being bound by any theory, it is believed that the buprenorphineachieves a sustained release profile in the absence of release-modifyingagents as a result of its low solubility in the aqueous environment inthe subcutaneous space and the manner in which it precipitates out ofthe organic solvent or solvent mixture to form a distinct depot in thesubcutaneous space in a living body.

Further modifications and improvements can be made without departingfrom the scope of the invention described herein.

The invention is further illustrated by the following numbered clauses.

-   -   1. A composition comprising a solution of 5-55 wt % of        buprenorphine dissolved in a polar aprotic solvent selected from        N-methyl-2-pyrrolidone (NMP), dimethyl acetamide (DMAC), or        dimethyl sulfoxide (DMSO) wherein the composition does not        comprise any biocompatible or biodegradable polymer.    -   2. A composition of clause 1 wherein the composition comprises        from 10-50 wt % buprenorphine.    -   3. A composition of clause 2 wherein the composition comprises        20-40 wt % buprenorphine.    -   4. A composition of clause 3 wherein the composition comprises        30-40 wt % buprenorphine.    -   5. A composition of clause 1 wherein the buprenorphine is        present as the free base (unprotonated) form or as a        pharmaceutically acceptable salt.    -   6. A composition of clause 1 wherein the composition comprises        up to 500 mg of buprenorphine.    -   7. A composition of clause 6 wherein the composition comprises        up to 500 mg of buprenorphine in a 1 cc solution.    -   8. A composition of clause 6 wherein the composition comprises        from 150-300 mg of buprenorphine.    -   9. A composition of clause 8 wherein the composition comprises        from 150-300 mg of buprenorphine in 1 cc or less solution.    -   10. A composition of clause 6 wherein the composition comprises        from 10-50 mg of buprenorphine.    -   11. A composition of clause 10 wherein the composition comprises        from 10-50 mg of buprenorphine in 0.2 cc or less solution.    -   12. A composition of clause 1 wherein the composition further        comprises up to 10% by weight of water.    -   13. A composition of clause 1 wherein the composition further        comprises a glycol up to 70% by weight.    -   14. A composition of clause 13 wherein the amount of glycol is        from 20-60% of the solvent mixture by weight.    -   15. A composition of clause 14 wherein the amount of glycol is        from 20-40% of the solvent mixture by weight.    -   16. A composition of clause 15 wherein the amount of glycol is        from 30-40% of the solvent mixture by weight.    -   17. A composition of clause 13 wherein the glycol is selected        from PEG300, PEG400 or propylene glycol.    -   18. A composition of clause 13 wherein the ratio of polar        aprotic solvent to glycol can be from 0.4:1 to 4:1.    -   19. A composition of clause 18 wherein the ratio is from 0.65:1        to 2.5:1.    -   20. A composition of clause 19 wherein the ratio is from 1:1 to        1.5:1.    -   21. A composition of clause 13 wherein the ratio of        buprenorphine to glycol is from 0.15:1 to 5:1.    -   22. A composition of clause 21 wherein the ratio is from 0.4:1        to 3.5:1.    -   23. A composition of clause 21 wherein the ratio is from 0.5:1        to 1:1.    -   24. A composition of clause 13 wherein the composition comprises        buprenorphine, a solvent selected from N-methyl-2-pyrrolidone        (NMP), dimethyl acetamide (DMAC), or dimethyl sulfoxide (DMSO)        and a glycol selected from PEG300, PEG400 or propylene glycol in        a ratio of from 1:3:7 to 1:0.5:0.1.    -   25. A composition of clause 24 wherein the ratio is from 1:2:2        to 1:1:0.4.    -   26. A composition of clause 24 wherein the ratio is selected        from 1:2.7:6.3, 1:1.5:1.5, 1:1.4:0.93, 1:1.05:0.45 or 1:0.8:0.2.    -   27. A composition of clause 24 wherein the composition consists        essentially of buprenorphine, N-methyl-2-pyrrolidone (NMP) and        PEG 400 in a ratio of from 1:3:7 to 1:0.5:0.1.    -   28. A composition of clause 27 wherein the ratio is from 1:2:2        to 1:1:0.4.    -   29. A composition of clause 27 wherein the ratio is selected        from 1:2.7:6.3, 1:1.5:1.5, 1:1.4:0.93, 1:1.05:0.45 or 1:0.8:0.2.    -   30. A composition of clause 1 wherein the composition further        comprises one or more pharmaceutically acceptable stabilizing        antioxidant agents such as ascorbic acid, vitamin E, BHT, BHA        which can enhance buprenorphine stability.    -   31. A method of treating a patient for opioid dependence or pain        relief comprising administering subcutaneously a composition of        clause 1.    -   32. A method of clause 31 wherein the method provides treatment        for opioid dependence or pain relief over a period of at least        30 days.    -   33. A method of clause 31 wherein the method provides treatment        for opioid dependence or pain relief over a period up to 3        months.    -   34. A method of clause 31 wherein the method provides a        therapeutically effective dosage of the buprenorphine from about        0.10 mg to about 10 milligrams (mg) per day.    -   35. A method of clause 31 wherein the method provides a        therapeutically effective level of the buprenorphine within        about one day after administration of the composition; and        wherein the therapeutically effective dosage of the        buprenorphine, or a pharmaceutical acceptable salt thereof is        delivered for at least one month after administration of the        composition, or up to 3 months after administration of the        composition.

The invention claimed is:
 1. A pharmaceutical solution consisting of:(i) at least 8 wt % buprenorphine in the form of a free base or apharmaceutically acceptable salt, and (ii) N-methyl-2-pyrrolidone,dimethyl acetamide, dimethyl sulfoxide, or a combination of two or morethereof.
 2. The solution of claim 1, wherein the buprenorphine ispresent in an amount of about 10 wt % to about 55 wt %.
 3. Apharmaceutical solution comprising: (i) at least 8 wt % buprenorphine inthe form of a free base or a pharmaceutically acceptable salt; (ii)N-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide, or acombination of two or more thereof; and (iii) polyethylene glycol in anamount from about 20% by weight to about 60% by weight of the mixture of(ii) and (iii).
 4. The solution of claim 3, wherein the polyethyleneglycol is present in an amount from about 20% by weight to about 40% byweight of the mixture of (ii) and (iii).
 5. The solution of claim 3,wherein the weight ratio of (ii) to (iii) is from 0.4:1 to 4:1.
 6. Thesolution of claim 3, wherein the weight ratio of (ii) to (iii) is from1:1 to 1.5:1.
 7. The solution of claim 3, wherein the weight ratio of(i) to (iii) is from 0.15:1 to 5:1.
 8. The solution of claim 3, whereinthe weight ratio of (i) to (iii) is from 0.5:1 to 1:1.
 9. The solutionof claim 3, wherein the buprenorphine is present in an amount of about10 wt % to about 55 wt %.
 10. The solution of claim 3, wherein thebuprenorphine is present in an amount of about 15 wt % to about 50 wt %.11. The solution of claim 3, wherein the polyethylene glycol has anaverage molecular weight of about 100 to about 1,000.
 12. The solutionof claim 11, wherein the polyethylene glycol has an average molecularweight of about 300 or about
 400. 13. The solution of claim 3, wherein(ii) is N-methyl-2-pyrrolidone.
 14. An injectable pharmaceuticalsolution comprising: (i) about 15 wt % to about 55 wt % of buprenorphinein the form of a free base or a pharmaceutically acceptable salt; (ii)N-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide, or acombination of two or more thereof; and (iii) polyethylene glycol,propylene glycol, or a combination thereof; wherein the weight ratio of(i):(ii):(iii) is from about 1:2.7:6.3 to about 1:0.74:0.08.
 15. Thesolution of claim 14, wherein (iii) is polyethylene glycol having anaverage molecular weight of about 100 to about 1,000.
 16. The solutionof claim 14, wherein the weight ratio of (i):(ii):(iii) is 1:2:2 to1:1:0.4.
 17. The solution of claim 14, wherein (i) is buprenorphine inthe form of the free base, (ii) is N-methyl-2-pyrrolidone; and (iii) ispolyethylene glycol having an average molecular weight of about 300 orabout
 400. 18. The solution of claim 14 consisting of (i), (ii), and(iii).
 19. The solution of claim 14, wherein (i) is buprenorphine in theform of the free base, (ii) is N-methyl-2-pyrrolidone, and (iii) ispolyethylene glycol.
 20. A method of treating opioid dependence or painin a patient in need thereof comprising administering a therapeuticallyeffective amount of the pharmaceutical solution of claim 3 to thepatient to treat the opioid dependence or pain.
 21. The method of claim20, wherein the solution is administered to the patient by subcutaneousinjection once per month.
 22. The method of claim 20, wherein thesolution is administered to the patient by subcutaneous injection onceevery three months.
 23. The method of claim 20 for treating opioiddependence.
 24. The solution of claim 3, wherein the buprenorphine is inthe form of the free base.
 25. The solution of claim 14, wherein (ii) isN-methyl-2-pyrrolidone.
 26. The solution of claim 3, comprising (i)about 30 wt % to about 50 wt % of buprenorphine in the form of the freebase; (ii) N-methyl-2-pyrrolidone; and (iii) polyethylene glycol,wherein the polyethylene glycol is present in an amount of about 20 wt %to about 40 wt % of the mixture of (ii) and (iii).
 27. The solution ofclaim 26, wherein the polyethylene glycol has an average molecularweight of about 300 or about
 400. 28. The solution of claim 3,comprising (i) about 20 wt % to about 55 wt % of buprenorphine in theform of the free base; (ii) N-methyl-2-pyrrolidone; and (iii)polyethylene glycol, wherein the polyethylene glycol is present in anamount of about 20 wt % to about 40 wt % of the mixture of (ii) and(iii).
 29. The solution of claim 28, wherein the polyethylene glycol hasan average molecular weight of about 300 or about
 400. 30. The solutionof claim 3, wherein the weight ratio of (ii) to (iii) is 0.65:1 to2.5:1.
 31. The solution of claim 3, wherein the weight ratio of (i) to(iii) is 0.4:1 to 3.5:1.
 32. The solution of claim 3, wherein thepolyethylene glycol has an average molecular weight of about 200 toabout
 500. 33. The solution of claim 14, wherein (i) is buprenorphine inthe form of the free base; (ii) is N-methyl-2-pyrrolidone, and (iii) ispolyethylene glycol.
 34. The solution of claim 14, wherein the weightratio of (ii) to (iii) is from 0.4:1 to 4:1.
 35. The solution of claim14, wherein the weight ratio of (ii) to (iii) is 0.65:1 to 2.5:1. 36.The solution of claim 14, wherein the weight ratio of (i) to (iii) isfrom 0.15:1 to 5:1.
 37. The solution of claim 14, wherein the weightratio of (i) to (iii) is 0.4:1 to 3.5:1.
 38. A method of treating opioiddependence or pain in a patient in need thereof, the method comprisingadministering to the patient a therapeutically effective amount of thesolution of claim 14 to treat the opioid dependence or pain.
 39. Themethod of claim 38, wherein the solution is administered to the patientonce per month by subcutaneous injection to treat opioid dependence. 40.A method of treating opioid dependence or pain in a patient in needthereof, the method comprising subcutaneously injecting into the patienta therapeutically effective amount of a solution to treat the opioiddependence or pain; wherein the solution comprises (i) buprenorphine inthe form of a free base or a pharmaceutically acceptable salt; (ii)N-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide, or acombination of two or more thereof; and (iii) polyethylene glycol,propylene glycol, or a combination thereof.
 41. The method of claim 40,wherein the solution is administered to the patient once per month oronce every three months.
 42. The method of claim 40 for treating opioiddependence.
 43. The method of claim 40, wherein the solution comprises:(i) buprenorphine in the form of the free base; (ii)N-methyl-2-pyrrolidone; and (iii) polyethylene glycol.
 44. Apharmaceutical solution consisting essentially of: (i) at least 8 wt %buprenorphine in the form of a free base or a pharmaceuticallyacceptable salt; (ii) N-methyl-2-pyrrolidone, dimethyl acetamide,dimethyl sulfoxide, or a combination of two or more thereof; and (iii)polyethylene glycol.
 45. The pharmaceutical solution of claim 44,consisting of (i), (ii), and (iii).
 46. A pharmaceutical solutioncomprising: (i) buprenorphine in the form of a free base or apharmaceutically acceptable salt; (ii) N-methyl-2-pyrrolidone, dimethylacetamide, dimethyl sulfoxide, or a combination of two or more thereof;(iii) polyethylene glycol, propylene glycol, or a combination thereof;wherein the weight ratio of (i):(ii):(iii) is from 1:2.7:6.3 to1:0.74:0.08; and wherein the pharmaceutical solution does not comprise abiodegradable polymer.
 47. The pharmaceutical solution of claim 46,wherein the biodegradable polymer comprises a polyester, a polylactide,a polyglycolide, a polycaprolactone, a polyanhydride, a polyamide, apolyurethane, a polyesteramide, a polydioxanone, a polyacetal, apolyketal, a polycarbonate, a polyorthocarbonate, a polyorthoester, apolyphosphoester, a polyphosphazene, a polyhydroxybutyrate, apolyhydroxyvalerate, a polyalkylene oxalate, a polyalkylene succinate, apoly(malic acid), a poly(amino acids), copolymers, terpolymers,combinations, or mixtures thereof.
 48. A pharmaceutical solutioncomprising: (i) at least 8 wt % buprenorphine in the form of a free baseor a pharmaceutically acceptable salt; (ii) N-methyl-2-pyrrolidone,dimethyl acetamide, dimethyl sulfoxide, or a combination of two or morethereof; and (iii) polyethylene glycol; wherein the pharmaceuticalsolution does not comprise a biodegradable polymer.
 49. A pharmaceuticalsolution comprising: (i) at least 8 wt % buprenorphine in the form of afree base or a pharmaceutically acceptable salt; (ii)N-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl sulfoxide, or acombination of two or more thereof; and (iii) polyethylene glycol;wherein the pharmaceutical solution does not comprise a polyester, apolylactide, a polyglycolide, a polycaprolactone, a polyanhydride, apolyamide, a polyurethane, a polyesteramide, a polydioxanone, apolyacetal, a polyketal, a polycarbonate, a polyorthocarbonate, apolyorthoester, a polyphosphoester, a polyphosphazene, apolyhydroxybutyrate, a polyhydroxyvalerate, a polyalkylene oxalate, apolyalkylene succinate, a poly(malic acid), a poly(amino acids),copolymers, terpolymers, combinations, or mixtures thereof.